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1108
Clinical Investigation
Long-term Serial Changes in Left Ventricular
Function and Reversal of Ventricular
Dilatation After Valve Replacement for
Chronic Aortic Regurgitation
Robert 0. Bonow, MD, Joseph T. Dodd, MD, Barry J. Maron, MD,
Patrick T. O'Gara, MD, Gale G. White, RN, Charles L. McIntosh, MD, PhD,
Richard E. Clark, MD, and Stephen E. Epstein, MD
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In most patients with aortic regurgitation, valve replacement results in reduction in left
ventricular dilatation and an increase in ejection fraction. To determine the relation between
serial changes in ventricular dilatation and changes in ejection fraction, we studied 61 patients
with chronic severe aortic regurgitation by echocardiography and radionuclide angiography
before, 6-8 months after, and 3-7 years after aortic valve replacement. Between preoperative
and early postoperative studies, left ventricular end-diastolic dimension decreased (from 75 ± 6
to 56±9 mm, p<0.001), peak systolic wall stress decreased (from 247±50 to 163±42
dynes 1031/cm2), and ejection fraction increased (from 43 ± 9% to 51±16%, p<0.001).
Between early and late postoperative studies, diastolic dimension and peak systolic wall stress
did not change, but ejection fraction increased further (to 56 ± 19%, p<0.001). The increase in
ejection fraction correlated with magnitude of reduction in diastolic dimension between
preoperative and early postoperative studies (r =0.63), between early and late postoperative
studies (r=0.54), and between preoperative and late postoperative studies (r=0.69). Late
increases in ejection fraction usually represented the continuation of an initial increase
occurring early after operation. Thus, short-term and long-term improvement in left ventricular systolic function after operation is related significantly to the early reduction in left
ventricular dilatation arising from correction of left ventricular volume overload. Moreover,
late improvement in ejection fraction occurs commonly in patients with an early increase in
ejection fraction after valve replacement but is unlikely to occur in patients with no change in
ejection fraction during the first 6 months after operation. (Circulation 1988;78:1108-1120)
X
In the majority of patients with chronic severe
aortic regurgitation, aortic valve replacement
results in a substantial reversal of left ventricular dilatation within the first few months of operation. 1-6 In such patients, this beneficial reduction
See p 1319
in left ventricular volume overload after operation is associated with a significant increase in left
ventricular systolic performance.4,913'16-20 In a subset of patients with preoperative left ventricular
dysfunction, however, valve replacement leads to
From the Cardiology Branch and Cardiac Surgery Branch,
National Heart, Lung, and Blood Institute, National Institutes of
Health, Bethesda, Maryland.
Address forcorrespondence: Robert 0. Bonow, MD, Building 10,
Room 7B15, National Institutes of Health, Bethesda, MD 20892.
Received December 29, 1987; revision accepted June 16, 1988.
less reduction in left ventricular diastolic volume and
no demonstrable improvement in systolic function
despite correction of valvular regurgitation,7,9'13'16-20
presumptive evidence for irreversible myocardial
dysfunction preceding operation. This change or lack
of change in left ventricular volume and function
occurring within the 1st year of aortic valve replacement is an important predictor of long-term postoperative prognosis.'6 However, serial long-term studies
of the effect of aortic valve replacement on left
ventricular systolic function have not been reported,
and the relation between the magnitude of reversal of
left ventricular dilatation and the increase in left
ventricular systolic performance, either short-term or
long-term after operation, has not been studied intensively. To address these issues, we studied a series of
patients undergoing aortic valve replacement for
chronic aortic regurgitation with preoperative and
Bonow et al Left Ventricular Function After Aortic Valve Replacement
serial long-term postoperative echocardiographic and
radionuclide angiographic evaluations.
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Patients and Methods
Patient Selection
We investigated the long-term effects of aortic
valve replacement on left ventricular function in 61
patients with chronic severe aortic regurgitation
undergoing operation between August 1976 and
December 1983. This study was initiated prospectively in 1976 because this was the year that radionuclide angiography became available for clinical
investigation at the National Heart, Lung, and
Blood Institute. There were 51 men and 10 women
in the study, ranging in age from 19 to 72 years
(mean, 43 years). Fifty-one patients underwent operation because of moderate to severe cardiac symptoms (New York Heart Association functional Class
III or IV). The other 10 patients were either asymptomatic or mildly symptomatic (functional Class I
or II); aortic valve replacement was recommended
in this subset because of consistent and reproducible evidence of depressed left ventricular contractile function at rest by both echocardiography and
radionuclide angiography. Patients were studied
before operation by echocardiography, radionuclide angiography, graded treadmill exercise testing, and cardiac catheterization. These studies were
complete in all patients except for one in whom
preoperative echocardiographic studies were of suboptimal quality. Patients returned 6-8 months after
operation for repeat echocardiograms, radionuclide
angiograms, and cardiac catheterization; studies
were complete except for four patients who did not
undergo repeat catheterization. Echocardiography
and radionuclide angiography were then repeated
during the long-term follow-up course, ranging from
3 to 7 years (mean, 5 years) after operation, except
for one patient who underwent late studies at 9 years.
To evaluate the time course of decrease in left ventricular dilatation, a subset of 31 patients also underwent
echocardiography at 10-14 days, as well as at 6-8
months and 3-7 years, after operation.
All preoperative studies were performed while
patients were taking no cardiac medications.
Although attempts were made to also perform postoperative studies free from cardiac drugs, this was
not always possible. The late studies were performed during drug therapy in 23 patients; 15 patients
received digoxin, six patients received a combination of digoxin and an arterial vasodilator, one
patient received hydralazine alone, and one patient
received propranolol alone.
Preoperative cardiac catheterization confirmed
the diagnosis of isolated severe aortic regurgitation
in 57 patients. Four patients had associated small
ventricular septal defects with left-to-right shunt
ratios less than 1.5: 1, which were closed at the time
of aortic valve replacement. Coronary arteriography
was
performed in all patients
over
35 years of
1109
age, as well as all patients under 35 years old with
angina pectoris; no patient had associated coronary
artery disease (more than 50% reduction in luminal
diameter) of any coronary artery. In addition, no
patient had associated mitral valve disease or disease of the ascending aorta requiring repair at the
time of aortic valve replacement.
The 61 patients were chosen for evaluation from
83 consecutive and prospectively studied patients
undergoing operation for isolated chronic severe
aortic regurgitation at our institution during the
timeframe of this study. Twenty-two patients were
not included in the present study because 1) one
patient did not undergo preoperative radionuclide
angiography, 2) five patients died before the 68-month postoperative evaluation could be performed, 3) two surviving patients did not return for
the 6-8-month reevaluation, 4) five patients died
between 6-8 months and 3 years, 5) four patients
developed prosthetic valve complications before
the late evaluation (three patients required repeat
aortic valve replacement), and 6) five surviving
patients refused or did not return for late studies.
Thus, although inferences can be drawn between
late changes in left ventricular function after operation
and long-term survival, a life-table survival analysis
on the basis of late postoperative left ventricular
function was not performed because of incomplete
data (arising predominantly because 14 patients died
or experienced prosthetic valve dysfunction before
long-term studies could be performed). However,
definitive survival analyses based on the preoperative
and early postoperative data in the first 80 of the 83
patients have been reported previously. 16
Echocardiography
M-mode echocardiograms were obtained as previously described.16 Measurements of left ventricular transverse dimensions were obtained with the
ultrasound beam directed through the left ventricle
just caudal to the tips of the mitral leaflets.6,2' The
end-diastolic left ventricular dimension was measured at the R wave of the electrocardiogram. The
upper limit of normal for end-diastolic dimension in
our laboratory is 55 mm. Interventricular septal
thickness was measured just below the tips of the
mitral leaflets, and left ventricular posterior wall
thickness was measured at the level of the mitral
leaflets. Because abnormal septal motion occurs
frequently after operation,6,21,22 left ventricular endsystolic dimension and fractional shortening were
not measured at either the early or late postoperative study. Thus, comparative serial echocardiographic measurements were confined to the left
ventricular end-diastolic dimension and wall thickness. From these primary measurements, we computed the ventricular radius: wall thickness ratio, an
index of the volume: mass ratio and a measure of
the degree to which left ventricular muscle mass is
appropriate for a given chamber volume,3'10,2324 by
dividing half the end-diastolic dimension by the
1110
Circulation Vol 78, No 5, November 1988
posterior wall thickness. In addition, we also estimated the peak systolic left ventricular meridional
wall stress from the systolic blood pressure (by cuff
sphygmomanometry, measured before radionuclide
angiography) and echocardiographic end-diastolic
dimension (D) and posterior wall thickness (h) with
the formula of Grossman et a123: peak systolic wall
stress = (systolic blood pressure x D)/[4h(1 + h/D)].
We did not attempt to compute end-systolic stress
because of the inability to measure end-systolic
ventricular pressure, the imprecision in determining
the instant of end systole by echocardiography, and
difficulties in measuring end-systolic dimension after
operation. Finally, the muscle cross-sectional area,
an index of left ventricular myocardial mass,3,4,11
was also computed: cross-sectional area= ir[D/
2+ h]2 - ir[D/212.
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Gated Blood Pool Cardiac Scintigraphy
Radionuclide angiography was performed with
patients in the supine position at rest and during
maximum symptom-limited bicycle exercise with a
previously defined protocol. 16,18 Preoperative exercise data were obtained in all but one patient who
was severely symptomatic at rest and could not
tolerate supine exercise.
Left ventricular ejection fraction was computed
from the scintigraphic data as previously described. 16,18
In addition, we also computed the regurgitant
volume: end-diastolic volume ratio25 from the resting studies. This was accomplished by first computing the ratio of left ventricular stroke volume to
right ventricular stroke volume,26 based on ventricular regions of interest constructed from a functional stroke volume image (computer subtraction
of the end-systolic image from the end-diastolic
image) and amplitude image (created by approximating each single-pixel time-activity curve with
the first harmonic of its temporal Fourier expansion27). The regurgitant fraction was then calculated
as regurgitant fraction = (stroke volume ratio - 1)/
(stroke volume ratio). The regurgitant volume enddiastolic volume ratio was then computed by multiplying the regurgitant fraction by the ejection
fraction. Technical limitations prevented calculation of this ratio in 12 of the 61 patients.
Graded Treadmill Exercise Testing
Preoperative exercise capacity was assessed with
the National Institutes of Health treadmill protocol. 16,28
In the first stage of this protocol, the treadmill is
driven at a constant speed of 2.2 mph at inclination of
0%. Every 2.5 minutes the inclination is increased
by 2.5% until a maximum of 22.5 minutes elapse,
resulting in a maximal workload of 2.2 mph at 20%
incline or approximately 8 MET. The inability to
obtain and complete this level of exercise was
defined as poor preoperative exercise tolerance. 16,28
Such impaired exercise tolerance was evident in 19
(31%) of 61 patients, including 11 (28%) of 39
patients in whom the preoperative ejection fraction
at rest was subnormal.
Aortic Valve Replacement
At operation, 28 patients received Starr-Edwards
prostheses (1260 series in 21, 2320 series in two, and
2400 series in five), 30 received Hancock porcine
bioprostheses Model 242, and three received BjorkShiley prostheses. Cardiopulmonary bypass was
performed with a disk or bubble oxygenator with a
flow rate of 2.2 1/min/m2. Cardiopulmonary bypass
times ranged from 55 to 158 minutes (mean, 84 ± 20
minutes), and aortic cross-clamp times ranged from
33 to 97 minutes (mean, 54 ± 15 minutes). In addition
to systemic hypothermia to 250 to 30° C in all patients,
myocardial preservation techniques included topical
40 iced saline with coronary perfusion in 27 patients
and hyperkalemic cold cardioplegia and topical
hypothermia in 34.
Postoperative Hemodynamic Studies
Postoperative left heart catheterization was performed with either the transseptal or the left ventricular puncture technique. Postoperative hemodynamic data demonstrated peak systolic gradients
across the prosthetic valve of less than 10 mm Hg in
40 patients, between 10 and 20 mm Hg in 11
patients, and 20 mm Hg or more in six patients. No
patient had a prosthetic valve gradient of more than
40 mm Hg. One patient with preoperative left
ventricular dysfunction had persistent severe (4 +
out of 4 +) aortic regurgitation 7 months after
operation because of a perivalvular leak. He underwent a second operation 8 months after the initial
valve replacement and is now asymptomatic 68
months after repair of the perivalvular leak. For
comparison with other patients, the 6-8-month data
on this patient were derived from studies obtained 6
months after the second operation, with long-term
follow-up data obtained 52 months later.
Statistical Methods
Analysis of serial echocardiographic and radionuclide angiographic data from the preoperative, early
postoperative, and late postoperative studies was
performed with analysis of variance of repeated
measures. Comparisons of data among subgroups of
patients were performed with analysis of variance.
The association between preoperative data and the
magnitude of postoperative change in left ventricular
dimensions and function was tested by linear regression analysis. The relation between changes in left
ventricular dimensions, wall stress or mass, and
changes in left ventricular ejection fraction after
operation was also tested with linear regression
analysis. Data are presented as mean + SD.
Results
Left ventricular end-diastolic dimension declined
significantly 6-8 months after aortic valve replacement compared with preoperative values (Table 1),
Bonow et al Left Ventricular Function After Aortic Valve Replacement
TABLE 1. Serial Changes in Left Ventricular Function After Aortic Valve keplacement
6-8 Months
Before
after operation
p
operation
All patients (n=61)
144 ± 24
<0.001
128 ±+18
Systolic blood pressure (mm Hg)
Echocardiographic data
LV end-diastolic dimension (mm)
75 ±+6
<0.001
56±9
13 + 2
NS
12±2
LV wall thickness (mm)
R: Th ratio
3.0±0.4
<0.001
2.4 ±0.5
247±50
<0.001
163 ±42
Peak systolic wall stress (kdynes/cm2)
26±7
LV muscle cross-sectional area (cm2)
35 ±6
<0.001
Radionuclide angiographic data
43±9
<0.001
51± 16
LV EF at rest (%)
36±10
51± 16
LV EF during exercise (%)*
<0.001
-8±7
<0.001
-0.7±8
Change in EF from rest to exercise*
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Patients with normal before-surgery LV EF at rest (n=22)
<0.05
141 ± 16
Systolic blood pressure (mm Hg)
Echocardiographic data
75 ±6
<0.001
LV end-diastolic dimension (mm)
13 ±1
NS
LV wall thickness (mm)
2.8±0.3
<0.001
R:Th ratio
230±55
<0.001
Peak systolic wall stress (kdynes/cm2)
36±4
<0.001
LV muscle cross-sectional area (cm2)
Radionuclide angiographic data
52±8
<0.001
LV EF at rest (%)
45 ±9
<0.001
LV EF during exercise (%)*
-7±8
<0.005
Change in EF from rest to exercise*
p
3-7 Years
after operation
<0.05
135 + 20
NS
NS
NS
NS
NS
55 + 10
12± 2
2.3 ± 0.5
168±48
26±7
<0.001
<0.005
NS
56 + 19
57 ± 20
0.7 ± 7
132 + 12
NS
131+17
53 + 6
13+ 2
2.1 +0.5
151±+30
26+5
<0.05
NS
NS
NS
NS
51+5
13±2
2.0±0.3
141± 30
26± 5
61± 11
61± 14
0.5 + 10
<0.01
<0.001
<0.05
68 ± 11
73 ± 11
5±6
<0.01
137 +-22
NS
NS
NS
NS
NS
57 + 11
12+2
2.4+ 0.5
183 +±49
26 ± 8
NS
NS
NS
49± 19
48± 19
-3 ±6
Patients with subnormal before-surgery LV EF at rest (n=39)
146±27
<0.001
127±+ 21
Systolic blood pressure (mm Hg)
Echocardiographic data
57-+ 9
75 ± 7
<0.001
LV end-diastolic dimension (mm)
12 +±2
12± 2
NS
LV wall thickness (mm)
2.5 ±0.5
3.1 ±0.4
<0.001
R: Th ratio
<0.001
170+±47
253 ± 51
Peak systolic wall stress (kdynes/cm2)
27 + 8
34±7
<0.001
LV muscle cross-sectional area (cm2)
Radionuclide angiographic data
<0.005
46+ 15
39 +±6
LV EF at rest (%)
46±15
<0.001
31±8
LV EF during exercise (%)*
-1±8
-8±6
<0.001
Change in EF from rest to exercise*
Data are mean ± SD.
LV, left ventricular; R: Th, radius:wall thickness ratio; EF, ejection fraction.
*Complete exercise radionuclide angiographic data were obtained in 56 patients.
decreasing from 75+6 to 56±9 mm (p<O.OOl).
There was no subsequent change in end-diastolic
dimension during further long-term studies. Data in
the 31 patient subgroup undergoing echocardiograms 10-14 days after operation, as well as at 6-8
months and 3-7 years after operation, demonstrated that the reduction in end-diastolic dimension
that was apparent several months after operation
occurred predominantly within only 2 weeks of
operation (Figure 1). End-diastolic dimension
decreased 21% from 77+6 to 618+ mm 2 weeks
after operation (p<0.001), with a further reduction
of only 5% (relative to preoperative values) to 57 + 10
1111
mm 6-8 months after operation and with no addi-
tional decrease during subsequent long-term studies.
Thus, 80% of the overall reduction in end-diastolic
dimension observed during long-term postoperative
evaluation occurred within 2 weeks of aortic valve
replacement.
In keeping with the postoperative reduction in
end-diastolic dimension and systolic blood pressure, peak systolic wall stress and muscle crosssectional area decreased significantly 6-8 months
after operation compared with preoperative values
(Table 1), with no further change during longer-term
follow-up. Changes in left ventricular radius: wall
1112
Circulation Vol 78, No 5, November 1988
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0L
10-14 days
Postop
Preop
6-8 months
3-7 years
Postop
Postop
FIGURE 1. Plot of serial changes in left ventricular
end-diastolic dimension before (preop) and after (postop)
valve replacement in 31 patients in whom early postoperative (10-14 days) echocardiograms were obtained.
The majority of patients manifested the greatest reduction in diastolic dimension within 2 weeks after operation.
e, Mean values.
thickness ratio reflected the significant decrease in
end-diastolic dimension at 6-8 months. The lack of
further change in this ratio at 3-7 years confirms the
muscle cross-sectional area data indicative of no
important change in left ventricular mass 6-8 months
after operation.
In contrast, left ventricular ejection fraction under
resting conditions, which increased significantly 68 months after operation (from 43 +9% to 51 + 16%,
p<O.00 1), increased further to 56 19% at the late
postoperative evaluation (p<0.001). Similarly, the
ejection fraction during maximum supine exercise,
well as the magnitude of change in ejection
fraction from rest to exercise, increased between
the preoperative and 6-8-month postoperative studies. Exercise ejection fraction increased further at
the late postoperative reevaluation although the
increment from rest to exercise remained fixed
(Table 1). The magnitude of the early and late
increase in ejection fraction was related to several
factors, principally the extent of postoperative reduction in left ventricular end-diastolic dimension.
as
Postoperative Change in Ejection Fraction in
Relation to Reduction in Left Ventricular
End-diastolic Dimension
The magnitude of increase in left ventricular
ejection fraction after operation, in patients with
as
0
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00
*
o8
e
0
0
-10
-20
-30
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-40
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o g
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Preop EF:
* Normal
0
o,
o
p
-10
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Subnormal
-40
-30
-20
10
CHANGE IN LV END-DIASTOLIC
DIMENSION (mm)
10
normal
Preop to Early Postop
Preop to Late Postop
0
LL
Uf)
O o-
a1)
0
70 e
50
40
30
well
as
those with subnormal
preopera-
FIGURE 2. Plots of change in left ventricular (LV) ejection fraction after operation plotted as a function of the
change in LV end-diastolic dimension. Data represent
changes from before (preop) to the 6-8-month postoperative study (early postop) and to the 3-7-year postoperative study (late postop). Different symbols differentiate
patients on the basis ofpreoperative ejection fraction (EF)
as indicated.
tive systolic function, correlated significantly with
the change in left ventricular end-diastolic dimension (Figure 2), both short-term (r= 0.63, p<0.001)
and long-term (r = 0.69, p<0.001). Although there was
no mean decrease in end-diastolic dimension between
6-8 months and 3-7 years for the total group, enddiastolic dimension significantly decreased (from 55 ± 9
to 52 + 8 mm, p<0.05) in those patients manifesting
an increase in ejection fraction after the 6-8 month
study. Moreover, for the entire group, changes in
ejection fraction from 6-8 months to 3-7 years also
correlated with changes in end-diastolic dimension
occurring during this period (r = 0.54, p<0.001).
Although the correlations were less strong, the
postoperative increase in ejection fraction was also
related to the reduction in peak systolic wall stress
(r = 0.42, p<O.01 for both short-term and long-term
changes, compared with preoperative values) and in
muscle cross-sectional area (r = 0.37 and r = 0.41 for
short-term and long-term changes, respectively;
p<0.01). Changes in ejection fraction and enddiastolic dimension were not related to changes in
blood pressure, either at the short-term (r 0.13 and
0.07, respectively) or long-term (r = 0.09 and 0.16,
respectively) reevaluations.
Preoperative Determinants of Postoperative
Reversal of Ventricular Dilatation and
Improved Systolic Function
The preoperative regurgitant volume: enddiastolic volume ratio was only weakly related to
the magnitude of decrease in end-diastolic dimen=
Bonow et al Left Ventricular Function After Aortic Valve Replacement
90
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11
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-1
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Preop
6-8 Months
Postop
3-7 Years
Postop
Preop
6-8 Months
Postop
3-7 Years
Postop
FIGURE 3. Plots of serial changes in left ventricular end-diastolic dimension and ejection fraction in 22 patients with
normal preoperative ejection fraction. Dashed line at 45% ejection fraction indicates the lower limit of normal for our
laboratory. Preop, before operation; postop, after operation.
sion after operation (r = 0.39 and 0.35 for short-term
and long-term changes, respectively; p<0.01). More
significant correlations developed when the analysis
was applied to patients with normal preoperative
ejection fractions (r= 0.56 and 0.49, respectively;
p<0.001), but there was no such correlation in
patients with systolic dysfunction (r = 0.25 and 0.18).
The magnitude of increase in ejection fraction at
rest after operation was unrelated to the preoperative regurgitant volume: end-diastolic volume ratio
(r = 0.17 and 0.20 for short-term and long-term
changes, respectively) and also was not related to
either the preoperative ejection fraction during exercise or the preoperative change in ejection fraction
occurring from rest to exercise. Similarly, the postoperative ejection fraction was not predicted by
preoperative values of resting ejection fraction or
echocardiographic ventricular cavity dimensions,
fractional shortening, muscle cross-sectional area,
or radius: wall thickness ratio. However, the magnitude of regression of dilatation and increase in
ejection fraction after operation differed among
patients with normal, compared with those with
subnormal, preoperative ejection fractions.
Patients with normal preoperative ejection fraction. In the 22 patients with normal preoperative left
ventricular systolic function at rest, end-diastolic
dimension decreased significantly by the early postoperative study, (from 75 + 6 to 53 + 6 mm) (Table 1
and Figure 3) with a further slight but significant
decrease to 51 5 mm between the early and late
postoperative studies. Despite the late reduction in
end-diastolic dimension, only three (30%) of 10
patients with persistent ventricular dilatation 6-8
months after operation had return of end-diastolic
dimension to normal at the late study. Similarly,
peak systolic wall stress and muscle cross-sectional
area decreased significantly by 6-8 months afteroperation but did not change thereafter.
Despite normal preoperative ejection fraction
(52 8%) in these patients, ejection fraction
increased to even higher levels reaching 61 ±11%
(p<0.OOl) 6-8 months after operation, with a further
increase to 68 + 11% (p<0.01) during the long-term
postoperative course (Table 1 and Figure 3). The
ejection fraction during exercise responded in similar
fashion, increasing from 45+9% to 61±14% (p
<0.001) at the 6-8-month postoperative study and to
72 11% (p<0.OOl) at the late postoperative reevaluation. Thus, the magnitude of the ejection fraction
response during exercise compared with resting values also increased, from -7 + 8% before operation to
0.5 + 10%o early after operation (p<O.OOS) and to
5±6% late after operation (p<0.05).
Patients with preoperative left ventricular systolic dysfunction. In the 39 patients with subnormal
preoperative ejection fraction at rest, changes in left
ventricular end-diastolic dimension after operation
followed similar trends as those observed in the
total patient cohort (Table 1), with a significant
Circulation Vol 78, No 5, November 1988
1114
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n
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6-8 Months
3-7 Years
Postop
Postop
Preop
6-8 Months
3-7 Years
Postop
Postop
FIGURE 4. Plots of serial changes in left ventricular end-diastolic dimension and ejection fraction in 39 patients with
subnormal preoperative ejection fraction. *Patients who died from chronic congestive heart failure after the late
postoperative study. Preop, postop, serial changes in left ventricular end-diastolic dimension before and after valve
replacement, respectively.
decrease 6-8 months after operation compared with
preoperative values (from 75 7 to 57 9 mm,
p<0.001) and with no further change during longterm follow-up (57 11 mm). Substantial reduction
in end-diastolic dimension after 6-8 months was
unusual (Figure 4). Of 18 patients with persistent
ventricular dilatation 6-8 months after operation,
only two (11%) had a decrease in diastolic dimension to normal (.55 mm) at the late follow-up
study. Peak systolic wall stress and muscle crosssectional area also did not change significantly
between the early and late postoperative studies.
The changes in ejection fraction occurring after
operation in these patients demonstrated a variable
response (Figure 4). In the majority of patients,
ejection fraction increased during the early postoperative course, but there were nonetheless many
patients in whom ejection fraction was unchanged
or decreased 6-8 months after operation. Moreover, there was no further significant change in
ejection between the early and late postoperative
studies (from 46±15% to 49+19%, p=NS). Six
patients with persistent left ventricular dysfunction
at the late study, including five with severe depression of ejection fraction (ejection fraction <30%),
subsequently died from chronic congestive heart
failure. These six patients also had persistent left
±
±
±
ventricular dilatation at the late postoperative study
(Figure 4).
In these patients with preoperative left ventricular dysfunction, late postoperative changes in ejection fraction were influenced importantly by the
directional changes in ejection fraction occurring
during the first 6-8 months after operation (Figure
5). In the subgroup manifesting an early increase in
ejection fraction 6-8 months after operation, ejection fraction increased further during subsequent
long-term follow-up in 20 of 24 patients, a mean
change from 54 + 5% to 61 + 7% (p<0.001); ejection
fraction was normal in 21 patients at the late postoperative evaluation. In contrast, patients with no
improvement in ejection fraction during the early
postoperative course demonstrated no subsequent
change during long-term follow-up; ejection fraction subsequently decreased in six of the 14 patients
after the early postoperative study and was normal
in only one patient at the long-term evaluation.
Although long-term follow-up periods varied among
patients, the direction and magnitude of these
changes in ejection fraction were not related to the
duration of follow-up. The late follow-up periods in
these two patient subgroups were similar at 58 + 13
and 60 14 months, respectively.
Patient subgroup analysis. Patients with subnormal preoperative left ventricular ejection fraction at
Bonow et al Left Ventricular Function After Aortic Valve Replacement
Early Increase in LV Ejection Fraction
No Early Increase in LV Ejection Fraction
90r
90r80 F
80 I
c
C
0
c
(3
0
CA.
0
70 1
0
C-
70
-
z
z
00
1115
0
60 F-
e
1-
60 -
cr.
U.
0
z
0
LU
z
50 F
0
50 H
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z
W
L
L p<0.001
20 F
w-
WJ
10
0
30 -
z
W
20 F
10 F
-
0
1
Preop
6-8 Months
Postop
3-7 Years
Postop
Preop
6-8 Months
Postop
3-7 Years
Postop
FIGURE 5. Plots of serial changes in left ventricular (LV) ejection fraction in patients with subnormal preoperative
ejection fractions. Patients are subdivided on the basis of an early increase in ejection fraction within 6-8 months after
operation (left panel) and no such early increase in ejection fraction (right panel). *Patients who died from chronic
congestive heart failure after the late postoperative study.
rest were divided into subgroups on the basis of
clinical data we have previously observed to provide
important information regarding postoperative
prognosis.13"6,25 This subgrouping was performed
initially on the basis of preoperative exercise tolerance as assessed by treadmill testing. Patients were
divided into those with preserved exercise tolerance
(completing the first stage of the National Institutes
of Health protocol) and those with impaired exercise
tolerance (who were unable to complete this stage
because of symptoms). Patients with preserved exercise tolerance were then further subdivided into two
groups on the basis of the duration of preoperative
left ventricular dysfunction, in those patients in
whom such information could be determined from
serial preoperative studies: 1) six patients with prolonged duration of left ventricular dysfunction (subnormal resting ejection fraction of more than 18
months before operation) and 2) 11 patients with a
brief duration of left ventricular dysfunction (normal
ejection fraction within 14 months of operation).
Patients with preoperative left ventricular systolic dysfunction and impaired exercise tolerance
and those with preserved exercise tolerance but
evidence of a prolonged duration of ventricular
dysfunction demonstrated no change in mean ejection fraction either early or late after operation
(Figure 6). All six patients who died after the late
postoperative studies were in these two subgroups;
five had impaired preoperative exercise tolerance,
and one had preserved exercise tolerance but prolonged preoperative left ventricular dysfunction. In
contrast, patients with preserved exercise tolerance,
and a brief duration of left ventricular dysfunction
manifested substantial increases in ejection fraction
early after operation with a further significant
increase during subsequent long-term follow-up.
The late ejection fractions in these latter patients
were similar to those observed in patients in whom
the preoperative resting ejection fraction was normal (Figure 6), and no patient in this subgroup died.
Similar trends were observed regarding postoperative changes in left ventricular end-diastolic dimension in these five patient subgroups (Figure 7).
Preoperative end-diastolic dimension did not differ
among subgroups, but diastolic dimension decreased
to a greater extent after operation in patients with
normal preoperative ejection fraction and in those
with a brief duration of left ventricular dysfunction
compared with patients with either impaired exercise tolerance or a prolonged duration of ventricular
dysfunction (p<O0O1). There were no important
changes in mean end-diastolic dimension after the
early postoperative study, and such changes achieved
1116
Circulation Vol 78, No 5, November 1988
LV DYSFUNCTION
Poor Exercise
Tolerance
Prolonged
Duration
LV DYSFUNCTION
Good Exercise
Tolerance
Unknown
Duration
NORMAL LV
EJECTION FRACTION
Brief
Duration
*~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
1
.&
c. 0
z
0IL
j~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..
U~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.....
Z~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.....
o
i i~ ~ ~~~~~~~~.
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ z......
o~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..
w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.....
-J~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..........
20~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.......
c
-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~...........
Preop 1 2 Preop1Preop
2
1
2
Postop PostopPostop
Preop~~~~~~~~~~~~~~~~~~~~~~~~~..... 1.2.Preop.1.
Postop~~~~~~~~~~~~~~~~~~~~~~~~~....... Postop..
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
FIGURE 6. Bar graph of left ventricular (LV) ejection fraction at rest before (preop) and after (postop) operation....in.......
patients with normal preoperative left ventricular ejection fraction at rest and in four patient
subnormal
preoperative ejection fraction. Postoperative data are shown at 6-8 months (1) and at 3subgroups.....with
7 years (2)..........
*sign....cant
differences.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.....
statistical significance only in patients with normal
preoperative ejection fractions. Thus, the important
influence of reversal of left ventricular dilatation on
improved systolic function was determined principally by reductions in end-diastolic dimension occurring during the first 6-8 months after operation.
Patient subgroups with different postoperative functional responses to operation did not differ with respect
to preoperative left ventricular end-diastolic dimension, hypertrophy, or peak systolic wall stress (Table
2). Patients with normal preoperative ejection fractions had significantly higher regurgitant volume: enddiastolic volume ratios than those with subnormal
ejection fractions, and, among patients with subnormal ejection fractions, this ratio was lowest in patients
with impaired exercise tolerance (Table 2). However,
the importance of this finding is unclear because the
regurgitant volume: end-diastolic volume ratio is related to ejection fraction (because reduced total stroke
volume relative to end-diastolic volume would result
in lower regurgitant volume), and the correlation
between these two variables was significant (r = 0.65).
Influence of Medical Therapy
In the 23 patients who underwent late postoperative studies while receiving cardioactive drugs,
drug therapy did not appear to affect left ventricular
function importantly. Ejection fraction increased
compared with the early postoperative study in 12
patients, was unchanged in one patient, and
decreased in 10 patients. Similarly, left ventricular
end-diastolic dimension decreased further compared with the early postoperative value in nine
patients but increased in 14 patients.
These 23 patients were then excluded, and the
serial postoperative data were reanalyzed in the
remaining 38 patients who were studied free from
cardiac drugs. The results were identical to those
observed in the total study population. In these 38
patients, ejection fraction at rest increased both
early (from 44 ± 9% to 53 + 14%, p<0.001) and late
(to 58 ± 17%, p<0.001). End-diastolic dimension
decreased initially (from 76 ± 7 to 55 ± 8 mm,
p<0.001) with no further change at the late postoperative study (54 ± 9 mm). Changes relative to preoperative data in end-diastolic dimension correlated
with changes in resting ejection fraction for both
early (r= 0.54, p<0.001) and late (r = 0.60, p<0.001)
postoperative data. Peak systolic wall stress decreased initially with no subsequent change after
the early postoperative study, and changes in wall
stress correlated only weakly with early and late
changes in ejection fraction (both, r= 0.39, p<0.01).
The late changes in ejection fraction were most
notable in patients with normal preoperative ejection fractions; ejection fraction increased from
59± 11% at the early study to 66±9% at the late
study (p<0.005). In contrast, there were no late
changes in ejection fraction (from 55±9% to
55+ 11%) in patients with subnormal preoperative
ejection fractions.
Bonow et al Left Ventricular Function After Aortic Valve Replacement
Prolonged
Duration
1001
NORMAL LV
EJECTION FRACTION
LV DYSFUNCTION
Good Exercise
Tolerance
LV DYSFUNCTION
Poor Exercise
Tolerance
1117
Bnef
Unknown
Duration
Duration
F*n r*E
T
z
0
U)
z
W
...
..........
0
...........
....
....
0
U,)
..........
.........
0
..........
.....
.........
z
W
...........
....
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Preop 1
2
Postop
Preop 1
2
Preop 1
Postop
........
2
Postop
Preop 1
2
Postop
Preop 1
2
Postop
FIGURE 7. Bar graph of change in echocardiographic left ventricular (LV) end-diastolic dimension in the five patient
subgroups. Data are displayed as in Figure 6. In addition to the significant changes shown (*), early and late
postoperative diastolic dimensions were significantly less in patients with normal preoperative ejection fractions and
those with brief duration of systolic dysfunction compared with patients with preoperative systolic dysfunction and either
poor exercise tolerance or prolonged duration of systolic dysfunction (p<0.01).
Discussion
Left ventricular systolic function is an important
determinant of long-term prognosis in patients with
chronic aortic regurgitation undergoing aortic valve
replacement. Patients with impaired preoperative left
ventricular function have a greater risk of developing
postoperative congestive heart failure and of dying
than do patients in whom preoperative left ventricular
function is normal.5,10,16,19,29-34 Importantly, numerous recent studies indicate that depressed left ventricular systolic performance may improve and, in some
patients, normalize after reversal of the volume overload by valve replacement.3,4A7,9,l1-20 These changes,
documented within the 1st year of operation, correlate with survival during the subsequent 4-5 years;
patients with normal postoperative systolic performance have an excellent prognosis, whereas survival
rates are reduced in patients with persistent left ventricular dysfunction.'6 The purpose of the current
study was to determine serial long-term changes in
left ventricular dilatation, mass, systolic wall stress,
and systolic function and to assess the preoperative
and early postoperative determinants of subsequent
late postoperative ventricular function.
Our data demonstrate a substantial decrease in left
ventricular end-diastolic dimension within 6-8 months
of operation (Table 1 and Figures 3 and 4). In the
majority of patients, the greatest reduction in enddiastolic dimension developed within only 14 days of
operation; 80%o of the overall decrease in diastolic
dimension observed during the long-term postoper-
ative course occurred within 2 weeks of valve replacement (Figure 1). These findings are strikingly similar
to the echocardiographic data reported by Schuler et
a14 and Carroll et all1 in smaller groups of patients, in
which 82% and 78%, respectively, of the overall
reduction in end-diastolic dimension after 1 year of
valve replacement occurred within the first few weeks
after operation.
In our patients, most exhibited no further change
in end-diastolic dimension after 6-8 months. Patients
with normal preoperative ejection fractions manifested a statistically significant decrease in diastolic
dimension after 6-8 months, but the mean decrease
in diastolic dimension was only 2 mm (Table 1 and
Figure 3). In patients with depressed preoperative
left ventricular systolic function, there was no mean
change in diastolic dimension after the 6-month
study, and important reductions in diastolic dimension during long-term follow-up were uncommon.
Only five (17%) of 28 patients with persistent left
ventricular dilatation at 6-8 months showed a further reduction in diastolic dimension to normal with
longer follow-up (Figures 3 and 4). These findings
are consistent with the angiographic data of Toussaint et a19 and the echocardiographic data of Fioretti et al,12 who also demonstrated that only a
minority of patients with persistent left ventricular
dilatation 6-12 months after operation manifest a
subsequent reduction in ventricular cavity size to
normal. Thus, all of the available information indicates that patients with persistent ventricular dila-
1118
Circulation Vol 78, No 5, November 1988
TABLE 2. Preoperative Data in Patient Subgroups
Patients with subnormal LV EF at rest
Patients with
normal LV
EF at rest
(n 22)
p*
NS
NS
All
patients
(n 39)
Good exercise tolerance
Brief
Unknown Prolonged
duration
duration
duration
(n= 11)
(n 11)
(n 6)
Patients with
poor exercise
tolerance
(n- 11)
54+9
146 28
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Age (yr)
43+13
46+13
43+13
43+13
38+9
137 30
Systolic blood pressure (mm Hg)
141+6
146+27
157+29
140+22
Echocardiographic data
75 ± 6
NS
75 7
75 4
75 6
76 ± 10
LV end-diastolic dimension (mm)
74 8
51 + 5
<0.001
56 ± 6
55 3
56 5
55 ± 8
LV end-systolic dimension (mm)
5 7
13 ± 1
NS
12 ± 2
12 1
12 1
12 ± 3
LV wall thickness (mm)
13 2
NS
3.1±0.4
3.1±0.3
3.3±0.6
2.8±0.3
3.1±0.4
R:Thratio
2.9±0.4
230 + 55
NS
252 ± 51
277 + 47
247 ± 53
243 ± 35
Peak systolic wall stress (kdynes/cm2)
239 ± 59
NS
34±7
34±5
34±3
33±12
Cross-sectional area (cm2)
35±8
36+4
Radionuclide angiographic data
52±8
LV EFat rest(%)
39±6
40±5
33±8t
42±3
t
41+3
LV EF during exercise (%)
45 ± 9
31 ± 8
30 10
32 ± 4
36 ± 8
28 ± 6
t
NS
-8±6
-7±8
-10±10
-6±5
Change in EF from rest to exercise
-8±3
-6±7
RV: EDV ratio at rest
0.34 + 0.09 <0.005 0.26 ± 0.08 0.31± 0.07 0.24±0.08 0.28 ±0.04 0.21 ±0.07t
±
Data are mean SD.
EF, ejection fraction; LV, left ventricular. R: Th, end-diastolic radius: wall thickness ratio; RV: EDV. regurgitant volume: enddiastolic volume ratio.
*Comparison between patients with normal ejection fraction and all patients with subnormal ejection fraction (unpaired t test).
tComparison not made since patient subgroups defined on basis of ejection fraction.
tSignificant difference compared to other subgroups with subnormal ejection fraction at rest (analysis of variance),
tation in the 1st year after operation have a high
likelihood of continuing ventricular dilatation during the long-term postoperative course. This has
important prognostic implications, because numerous studies indicate that persistent ventricular dilatation identifies patients at risk of subsequent death
from congestive heart failure,36,i16.35.36 as was the
case in this study (Figure 4). Because the greatest
reduction in end-diastolic dimension occurs within
2 weeks after operation, data relevant to long-term
prognosis may be obtained in many patients by
echocardiography before hospital discharge.
Levine and Gaasch25 postulated that the magnitude of reduction in end-diastolic dimension after
aortic valve replacement might be predicted on the
basis of the preoperative ratio of regurgitant volume
to end-diastolic volume. In our patients, this ratio
did not correlate well with the postoperative decrease
in end-diastolic dimension. However, in the subgroup with normal preoperative ejection fractions,
this ratio was significantly related to the postoperative reduction in end-diastolic dimension. The lack
of correlation among patients with subnormal preoperative ejection fraction suggests that irreversible
myocardial dysfunction, independently of the regurgitant volume, contributes in many such patients to
preoperative left ventricular dilatation. Hence, persistent ventricular dilatation occurs commonly in
patients with preoperative systolic dysfunction
(Figure 4), even in patients with a high regurgitant
volume: end-diastolic volume ratio.
Changes in peak systolic wall stress and myocardial
cross-sectional area paralleled those observed in left
ventricular end-diastolic dimension. These indexes of
left ventricular wall stress and hypertrophy decreased
substantially within 6-8 months after operation with
no further change during long-term follow-up.
In contrast to the lack of late changes in left
ventricular dilatation, wall stress, and mass, left
ventricular ejection fraction increased significantly
during both short-term and long-term follow-up
studies. Late improvement in ejection fraction during long-term follow-up usually represented the
continuation of an initial increase occurring early
after operation (Figure 5). These increases in ejection fraction, both short-term and long-term, were
significantly related to the magnitude of decrease in
end-diastolic dimension (Figure 2). Although improved systolic function was also related to reduction in peak systolic wall stress and to regression of
hypertrophy, the changes in ejection fraction correlated less strongly with changes in left ventricular
wall stress and mass than they did with changes in
end-diastolic dimension. Our methods did not allow
computation of end-systolic stress, a more pure
measure of the afterload affecting left ventricular
emptying than peak systolic wall stress.37 Nor could
we measure circumferential wall stress38 (because
of the lack of long-axis diameters from the M-mode
measurements). It is possible that changes in these
measures of systolic wall stress, reflecting reduced
afterload after operation, might have shown a closer
correlation to the postoperative changes in ejection
Bonow et al Left Ventricular Function After Aortic Valve Replacement
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
fraction. Nonetheless, our data clearly indicate that
afterload was increased before operation, consistent with previous reports,10,36-39 as end-diastolic
dimension and systolic blood pressure were elevated, resulting in increased peak systolic wall
stress. Postoperative reduction in these determinants of afterload was associated with improvement
in left ventricular ejection performance.
These data indicate that in many patients with left
ventricular dysfunction, systolic performance is
reversibly depressed on the basis of afterload excess
arising from the severe volume overload,40-42 and, in
these patients, systolic function responds favorably
to surgical removal of valvular regurgitation and to
reversal of ventricular dilatation. Of note, this effect
is evident also in patients with "normal" preoperative systolic function, in that ejection fraction
increases significantly after operation (Figure 3),
suggesting that ventricular performance in these
patients, although within normal limits, may also be
subject to afterload excess before operation. Ejection fraction continued to increase late after operation in many patients. In this particular subgroup,
characterized by late increases in ejection fraction,
there were also further significant decreases in enddiastolic dimension. Moreover, for the entire group,
the subsequent late changes in ejection fraction after
the early postoperative study also correlated with
simultaneous further changes in end-diastolic dimension. However, the correlation between changes in
ejection fraction and changes in diastolic dimension
occurring between 6-8 months and 3-7 years after
operation, although significant, was relatively weak
(r=0.54). Thus, it appears that additional factors,
other than decreases in left ventricular diastolic
volume and, therefore, wall stress, may contribute to
the late increase in ejection fraction. It is also possible that further reduction in cavity size along the long
axis of the left ventricle (resulting in reduced circumferential wall stress), which would not have been
sampled by our echocardiographic technique, could
account for the late increase in ejection fraction.
Patients manifesting the greatest reduction in
end-diastolic dimension after operation, hence those
with the greatest likelihood of early and late increases
in ejection fraction, were either those with normal
preoperative ejection fraction or those with depressed ejection fraction but preserved exercise
tolerance and only a brief duration of left ventricular dysfunction (Figures 6 and 7). We have previously demonstrated that such patients have an
excellent postoperative prognosis,16 and of all the
deaths that occurred in our total consecutive series
of 83 patients during the time frame of this study,
only one was in this subgroup of patients.
In contrast, among patients with preoperative left
ventricular dysfunction and reduced exercise tolerance or those with good, exercise tolerance but a
prolonged duration of preoperative systolic dysfunction, the magnitude of decrease in end-diastolic
dimension was less pronounced, and there was no
1119
significant change in ejection fraction after operation either short-term or long-term (Figures 6 and
7). These data indicate that depressed systolic performance in these latter patients is not related
purely to volume overload but also to a considerable extent to irreversible myocardial dysfunction
that will not improve despite technically successful
reversal of the regurgitant volume by valve replacement. Our previous analysis indicates that patients
with these preoperative characteristics have reduced
postoperative survival.'6 Indeed, all six deaths occurring in the current series after the late postoperative
studies occurred in these patients. In addition, of the
10 deaths occurring before late postoperative studies
(and thus not included in the current study), five
were in this subgroup of patients and four occurred
in the subgroup with left ventricular dysfunction of
unknown duration. Thus, among the 83 consecutive
patients undergoing aortic valve replacement during
the timeframe of this study, 15 of the 16 postoperative deaths occurred in patients with preoperative left
ventricular dysfunction and impaired exercise tolerance or with preoperative systolic dysfunction, the
duration of which was prolonged or unknown. The
current data indicate that such patients have a higher
risk of irreversible left ventricular dysfunction and
death after operation than do patients with preserved
exercise tolerance and only a brief duration of preoperative systolic dysfunction and are further evidence that patients with impaired left ventricular
systolic performance benefit from early operation.
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KEY WORDS * aortic regurgitation * aortic valve replacement
l eft ventricular function
Long-term serial changes in left ventricular function and reversal of ventricular
dilatation after valve replacement for chronic aortic regurgitation.
R O Bonow, J T Dodd, B J Maron, P T O'Gara, G G White, C L McIntosh, R E Clark and S E
Epstein
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Circulation. 1988;78:1108-1120
doi: 10.1161/01.CIR.78.5.1108
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